Selected Articles from This Issue

The potential therapeutic utility of targeting epigenetic processes has been demonstrated across multiple cancer types, but the epigenetic complexes responsible for differentiation state are not well understood in neuroblastoma. To address this, Cmarik and colleagues mined the Dependency Map for epigenetic complexes using the CORUM database and revealed an enrichment for PRC1.1 complex dependency in neuroblastoma. Analysis of PCGF1 knockout cells, a core subunit of PRC1.1, demonstrated PCGF1-deficeint cells had reduced growth capacity, and EdU and PI incorporation assays found these cells had reduced progression through the synthesis phase of the cell cycle. CUT&RUN and ChIP-seq analyses showed PRC1.1 localization in two patterns, a PRC1.1 and PRC2 complexes (PCGF1, RINGB1, EZH2 and H3K27me3), and PRC1.1 only (PCGF1, RINGB1, and H2AK119Ub). The authors also performed Gene Ontology analysis and GSEA for PCGF1-regulated genes, and found they were enriched in neuronal differentiation programs. Interrogation of PRC1.1 as a therapeutic target highlighted the PRC1.1 subunit USP7, and USP7 inhibition and USP7 knockout in neuroblastoma cell lines impaired growth and increased the expression of differentiation markers. USP7 inhibition impaired PRC1.1 by reducing expression of PCGF1 and KDM2B. Altogether, this study identifies the critical role of PRC1.1 in the transcriptional regulation of neuronal differentiation pathways and indicates that targeting the USP7-dependency in neuroblastoma may be therapeutically advantageous.BRCA1 and BRCA2 carriers have increased risk of gastric cancer, but there is limited understanding of the role of these genes in gastric cancer pathogenesis. To address this, Buckley and colleagues evaluated the biological differences in the gastric epithelium of BRCA1 and BRCA2 carriers and noncarriers. Patient-derived gastric organoids developed by the authors revealed increased formation of organoids formed from BRCA2 carriers for both the antrum and body than for the control. Conversely, BRCA1 organoids from the gastric body were observed as larger than their BRCA2 counterparts and controls. The authors also assessed the proliferative potential of BRCA1 and BRCA2 body organoids and found increased Ki-67 expression compared to the control. Double-stranded DNA damage was also found to be enhanced in BRCA1 and BRCA2 organoids, showing increased levels of γ-H2AX and 53BP1 immunolabeling and increased comet tail DNA. Interestingly, variant of allele analysis, chromosomal instability scores, mutational burden, HRD scores, and RT-qPCR of BRCA1 and BRCA2 organoids indicated no loss of heterozygosity, alluding to the potential for BRCA1 and BRCA2 haploinsufficiency in the gastric epithelium. Taken together, this study highlights the early events associated with gastric cancer risk among BRCA1 and BRCA2 carriers and supports further study of BRCA1/BRCA2 in gastric carcinogenesis.Lenvatinib resistance is commonly developed in hepatocellular carcinoma, but there are limited clinical approaches to circumvent this resistance. To address this, Chen and colleagues identified a resistance-associated protein axis and evaluated its utility as a therapeutic target. RNA sequencing and KEGG enrichment analysis of lenvatinib-resistant hepatocellular carcinoma cells and public datasets revealed an upregulation of USP43 in resistant cells. IHC analysis also showed enhanced expression of USP43 in lenvatinib-resistant hepatocellular carcinoma. Lenvatinib-resistant USP43 knockdown hepatocellular carcinoma cells demonstrated decreased resistance and proliferation, and reduced expression of phosphorylated AKT, phosphorylated BAD, and BCL-2. Coimmunoprecipitation and LC/MS identified an interaction between USP43 and MYH9 in lenvatinib-resistant hepatocellular carcinoma. Further analysis of this interaction using ubiquitination analysis found that USP43 drove K48-linked polyubiquitin chain removal on MYH9. The authors also observed a reversal of USP43 knockdown phenotypes upon MYH9 overexpression. The HTFtarget database, PROMO database, JASPAR database, and subsequent ChIP analysis identified ETS1 as promoter-binding regulatory molecule for USP43. Overall, this study demonstrates that the ETS/USP43/MYH9 axis is an important mediator of lenvatinib resistance in hepatoceullar carcinoma and proposes that this axis may be targeted to reverse resistance.